Hexafluoroisopropanol derivatives

Abstract

The invention is concerned with novel hexafluoroisopropanol derivatives of formula (I) wherein R 1 to R 6 , m and n are as defined in the description and in the claims, as well as physiologically acceptable salts and esters thereof. These compounds bind to LXR alpha and LXR beta and can be used as medicaments.

1. A compound of the formula (I): 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is hydrogen, halogen, or lower-alkyl; 
 R 2  is lower-alkyl, fluoro-lower-alkyl, cycloalkyl-lower-alkyl, or heterocyclyl-lower-alkyl; 
 R 3  is hydrogen, lower-alkyl, aryl, cycloalkyl, or heterocyclyl; 
 R 4  is hydrogen, hydroxy, lower-alkoxy, aryl-lower-alkoxy, or heterocyclyl-lower-alkoxy; 
 R 5  is hydrogen, lower-alkyl, aryl, or heterocyclyl; 
 R 6  is 
 
       
         
           
           
               
               
           
         
         R 7  is lower-alkyl or fluoro-lower-alkyl; 
         R 8  is phenyl which is optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxy, amino, halogen, lower-alkyl, fluoro-lower-alkyl, hydroxy-lower-alkyl, R 9 —O—C(O)—, R 10 R 11 NC(O)—, R 12 —O—C(O)-lower-alkyl, R 13 —O—C(O)-hydroxy-lower-alkyl, R 14 R 15 NC(O)-lower-alkyl, R 16 R 17 NC(O)-hydroxy-lower-alkyl, lower-alkoxy, aryl-lower-alkoxy, R 18 —O—C(O)-lower-alkoxy and R 19 R 20 NC(O)-lower-alkyoxy; 
         R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19  and R 20  independently from each other are hydrogen or lower-alkyl; 
         L is a single bond, lower-alkylene, or lower-alkenylene; 
         m is 0 to 3; 
         n is 0 or 1; 
         and pharmaceutically acceptable salts and esters thereof. 
       
     
     
       2. The compound according to  claim 1 , wherein R 1  is hydrogen or halogen. 
     
     
       3. The compound according to  claim 1 , wherein R 1  is hydrogen or chlorine. 
     
     
       4. The compound according to  claim 1 , wherein R 2  is lower-alkyl or fluoro-lower-alkyl. 
     
     
       5. The compound according to  claim 1 , wherein R 2  is ethyl or 2,2,2-trifluoro-ethyl. 
     
     
       6. The compound according to  claim 1 , wherein R 3  is hydrogen or aryl. 
     
     
       7. The compound according to  claim 1 , wherein R 3  is hydrogen or phenyl. 
     
     
       8. The compound according to  claim 1 , wherein R 3  is hydrogen. 
     
     
       9. The compound according to  claim 1 , wherein R 4  is hydrogen or hydroxy. 
     
     
       10. The compound according to  claim 1 , wherein R 5  is hydrogen. 
     
     
       11. The compound according to  claim 1 , wherein R 6  is 
       
         
           
           
               
               
           
         
         wherein R 7  is lower-alkyl; 
         R 8  is phenyl which is optionally substituted with a substituent selected from the group consisting of halogen, fluoro-lower-alkyl, R 9 —O—C(O)—, R 10 R 11 NC(O)— and aryl-lower-alkoxy; 
         R 9  is hydrogen or lower-alkyl; 
         R 10  and R 11 , independently from each other are hydrogen or lower-alkyl; 
         L is a single bond, lower-alkylene, or lower-alkenylene. 
       
     
     
       12. The compound according to  claims 11 , wherein R 7  is methyl. 
     
     
       13. The compound according to  claim 11 , wherein R 8  is phenyl substituted with fluoro-lower-alkyl, halogen, carboxy, or (lower-alkyl) 2 NC(O)—. 
     
     
       14. The compound according to  claim 11 , wherein R 8  is 3-trifluoromethyl-phenyl, 3-chloro-phenyl, 4-carboxy-phenyl, or 4-(CH 3 ) 2 NC(O)-phenyl. 
     
     
       15. The compound according to  claim 11 , wherein L is a single bond. 
     
     
       16. The compound according to  claim 1 , wherein m is 0 to 2. 
     
     
       17. The compound according to  claim 1 , wherein m is 0. 
     
     
       18. The compound according to  claim 1 , wherein n is 0. 
     
     
       19. The compound according to  claim 1 , selected from the group consisting of:
 1,1,1,3,3,3-Hexafluoro-2-{4-[[5-methyl-2-(3-trifluoromethyl-phenyl)-oxazol-4-ylmethyl]-(2,2,2-trifluoro-ethyl)-amino]-phenyl}-propan-2-ol, 
 2-{4-[[2-(3-Chloro-phenyl)-5-methyl-oxazol-4-ylmethyl]-(2,2,2-trifluoro-ethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol, 
 2-(4-{Ethyl-[5-methyl-2-(3-trifluoromethyl-phenyl)-oxazol-4-ylmethyl]-amino}-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol, 
 2-(4-{[2-(3-Chloro-phenyl)-5-methyl-oxazol-4-ylmethyl]-ethyl-amino}-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol, 
 2-(3-Chloro-4-{ethyl-[5-methyl-2-(3-trifluoromethyl-phenyl)-oxazol-4-ylmethyl]-amino}-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol, 
 2-(3-Chloro-4-{[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethyl]-ethyl-amino}-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol, 
 2-(4-{[2-(3-Benzyloxy-phenyl)-5-methyl-oxazol-4-ylmethyl]-ethyl-amino}-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol, 
 2-(4-{[2-(4-Benzyloxy-phenyl)-5-methyl-oxazol-4-ylmethyl]-ethyl-amino}-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol, 
 3-[4-({Ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-benzoic acid methyl ester, 
 4-[4-({Ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-benzoic acid methyl ester, 
 3-[4-({Ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-benzoic acid, 
 4-[4-({Ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-benzoic acid, 
 3-[4-({Ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-N-methyl-benzamide, 
 3-[4-({Ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-N,N-dimethyl-benzamide, 
 3-[4-({Ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-benzamide, 
 4-[4-({Ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-N-methyl-benzamide, 
 4-[4-({Ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-N,N-dimethyl-benzamide, 
 4-[4-({Ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-benzamide, 
 2-{4-[(2-Benzyl-5-methyl-oxazol-4-ylmethyl)-ethyl-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol, 
 2-(4-{Ethyl-[5-methyl-2-((E)-styryl)-oxazol-4-ylmethyl]-amino}-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol, and 
 2-{4-[ethyl-(5-methyl-2-phenethyl-oxazol-4-ylmethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol, 
 
       and pharmaceutically acceptable salts and esters thereof. 
     
     
       20. The compound according to  claim 1 , selected from the group consisting of:
 2-(4-{Ethyl-[5-methyl-2-(3-trifluoromethyl-phenyl)-oxazol-4-ylmethyl]-amino}-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol, 
 2-(4-{[2-(3-Chloro-phenyl)-5-methyl-oxazol-4-ylmethyl]-ethyl-amino}-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol, 
 4-[4-({Ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-benzoic acid, and 
 4-[4-({Ethyl-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-methyl)-5-methyl-oxazol-2-yl]-N,N-dimethyl-benzamide, 
 
       and pharmaceutically acceptable salts and esters thereof. 
     
     
       21. A process for the manufacture of compounds of formula (I) as defined in  claim 1 , comprising the step of:
 a) reacting a compound of formula (II): 
 
       
         
           
           
               
               
           
         
          with a compound LG-CHR 3 —(CH 2 ) m —(CR 4 R 5 ) n —R 6 , or 
         b) reacting a compound of formula (III): 
       
       
         
           
           
               
               
           
         
          with a compound LG-R 2 , 
       
       wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , m and n are as defined in any of  claims 1 - 23  and LG is a leaving group. 
     
     
       22. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to  claim 1  and a pharmaceutically acceptable carrier and/or adjuvant.